P760: PATTERNS OF HYPOMETHYLATING AGENT FAILURE IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES
Authors: K. Chien, K. Kim, Z. Li, R. Kanagal Shamanna, F. Ong, G. Montalban Bravo, T. Kadia, E. Jabbour, N. Pemmaraju, D. Hammond, N. Short, F. Ravandi, Y. Alvarado, S. Pierce, X. Q. Dong, H. Kantarjian, G. Garcia-Manero
Journal: HemaSphere (2022)

Background: Hypomethylating agents (HMA), such as azacitidine and decitabine, are the current standard-of-care for patients (pts) with myelodysplastic syndrome (MDS). Though HMA improve cytopenias and delay progression of disease, most pts eventually response to these agents with poor survival outcomes afterward. This poses significant treatment challenges after HMA failure (HMA-F) and an increased risk of transformation to acute myeloid leukemia (AML). Aims: Here, we assess the clinicopathologic characteristics and outcomes of pts with HMA-F MDS. Methods: We retrospectively evaluated all pts with MDS seen at a single tertiary cancer center from July 2017 to July 2021 and identified those who were previously untreated and later developed HMA-F. Pt characteristics, laboratory values, and bone marrow (BM) data, including cytogenetics and next generation sequencing (NGS), were assessed at both diagnosis and the time of HMA-F. Genomic DNA was extracted from whole BM aspirate samples and subject to 28- (n=12) or 81-gene (n=131) target PCR-based sequencing using a NGS platform at diagnosis and an 81-gene NGS panel (n=85) at the time of HMA-F. Survival data was updated in January 2022. Results: Out of 799 untreated MDS pts, 147 pts (32%) developed HMA-F with a median follow-up time of 44.0 months (mo) from diagnosis. Baseline pt characteristics and subsequent treatment are summarized in Table 1. The median age was 71 with therapy-related MDS (t-MDS) in 37%. At diagnosis, most pts had higher-risk MDS with IPSS-R high (29%) or very high (39%) disease, and complex karyotype was seen in 44%. The median number of mutations identified was 2 with TP53 (44%) and ASXL1 (21%) the most frequently discovered mutations. Regarding HMA therapy, 67% received HMA monotherapy and 33% received HMA in combination with various agents. The median number of cycles of HMAs received was 7 (range: 1-37). At the time of HMA-F, pts presented with higher BM blasts (6% vs 10%, p<0.001) and lower platelet counts (63 K/µL vs 36 K/µL, p<0.001) than at diagnosis. The median number of cytogenetic abnormalities increased from 1 to 2 with no change in the median number of mutations from diagnosis to HMA-F, but both had significant increases by paired t-test (p<0.001). The median time from diagnosis to HMA-F was 10.8 mo, and the median overall survival (mOS) from HMA-F was 6.8 mo (95% CI: 5.4, 9.0). Survival was well-stratified by both IPSS-R at diagnosis (14.6 mo in lower-risk MDS vs 5.4 mo in higher-risk MDS, p=0.001) and at HMA-F (11.4 mo in lower-risk MDS vs 3.5 mo in higher-risk MDS, p<0.001). TP53 mutations at diagnosis (HR 3.02, p<0.001) and t-MDS (HR 2.50, p<0.001) were associated with shorter mOS. In pts with higher-risk MDS, initial response to HMA therapy (7.2 mo in responders vs 2.7 mo in non-responders, p=0.011) and stem cell transplantation at HMA-F (4.7 mo in non-transplanted vs not reached in transplanted, p<0.001) were associated with improved survival. Progression to acute myeloid leukemia (AML) was seen in 72 pts (49%), and the mOS from the time of AML diagnosis was 3.4 mo. Image:Summary/Conclusion: Pts with HMA-F MDS have high-risk features, including poor cytogenetics and adverse mutations, and are often therapy-related. At the time of HMA-F, patients present with higher BM blasts, worsening thrombocytopenia, and more cytogenetic abnormalities and mutations. Unfortunately, after failure of HMA, pts have frequent transformation to AML and dismal overall survival. Further understanding of the underlying biology of HMA-F MDS is warranted with an urgent need for therapeutic interventions after failure of HMA therapy.